KR20070032619A - Combination Therapeutics of Iloprost for the Treatment of Pulmonary Hypertension - Google Patents

Abstract

Preferred embodiments of the present invention relate to novel combination therapies and methods for treating pulmonary arterial hypertension. More particularly, the present invention relates to the use of a combination of iloprost and at least one additive selected from the group consisting of endothelin receptor antagonists and PDE inhibitors.

Pulmonary arterial hypertension, PAH, iloprost, endothelin receptor antagonist, PDE inhibitor, combination therapy

Description

ILOPROST IN COMBINATION THERAPIES FOR THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION}

The present invention relates to the use of iloprost in combination with one or more additives, preferably endothelin receptor antagonists and / or PDE inhibitors, for treating and / or preventing pulmonary hypertension. .

Pulmonary arterial hypertension (PAH) is a debilitating disease characterized by an increase in pulmonary vascular resistance leading to right ventricular failure and death. Pulmonary hypertension that develops without an external cause is called primary pulmonary hypertension (PPH). Recently, various pathological changes associated with these diseases have been characterized as including vasoconstriction, vascular remodeling (eg, proliferation of both the middle and inner linings of pulmonary resistance vessels) and thrombosis of the site of development (eg, D ' Alonzo, GE et al. 1991 Ann Intern Med 115: 343-349; Palevslcy, HI et al. 1989 Circulation 80: 1207-1221 Rubin, LJ 1997 N Engl J Med 336: 111-117; Wagenvoort, CA & Wagenvoort, N 1970 Circulation 42: 1163-1184; Wood, P. 1958 Br Heart J 20: 557-570). Impairment of vascular and endothelial homeostasis is evidenced by decreased synthesis of prostacyclin (PGI ₂ ), reduced thromboxane production, decreased formation of nitric oxide and increased synthesis of endothelin-1 (see Giaid, A. & Saleh, D. 1995 N Engl J Med 333: 214-221; Xue, C & Johns, RA 1995 N Engl J Med 333: 1642-1644). In primary pulmonary hypertension, free calcium concentrations between cells of vascular smooth muscle cells of the pulmonary artery have been reported to be elevated.

Current treatment of pulmonary hypertension is unsatisfactory. Such treatments typically include calcium channel antagonists, prostacyclins, endothelin receptor antagonists, and long-term anticoagulant therapies. However, each treatment involves limitations and side effects.

As a result, a novel, preferably low dose, active agent for the treatment of PAH, which shows a favorable profile in terms of effectiveness in patients at different stages of PAH with no or almost no side effects (ie less toxicity). The need for combination therapy has long been demanded.

(Summary of invention)

Therapeutic combinations for the treatment of PAH are disclosed in accordance with aspects of the present invention. Such combination therapeutics contain one or more additives selected from the group consisting of prostacyclin and endothelin receptor antagonists, PDE inhibitors and calcium channel blockers, wherein the prostacyclin and one or more additives comprise PAH and Provided in an amount sufficient to ameliorate one or more of the symptoms associated with it.

In one embodiment, the prostacyclin is selected from the group consisting of iloprost, treprostinol, and veraprost. In another embodiment, the endothelin receptor antagonist is selected from the group consisting of bosentane, citaxentane, and ambricentan. In another embodiment, the prostacyclin is iloprost and the at least one additive is bosentan. In another embodiment, iloprost is aerosolized. In another embodiment, the at least one additive is a PDE inhibitor selected from the group consisting of sildenafil (tradename Viagra), tadalafil (trademark Cialis) and vardenafil (trademark LEVITRA).

A method of treating PAH is disclosed. Such methods include administering an effective amount of a prostacyclin and a combination therapeutic containing one or more additives selected from the group consisting of endothelin receptor antagonists, PDE inhibitors and calcium channel blockers. In one preferred embodiment, the method comprises administering iloprost in combination with one or more additives selected from the group consisting of bosentan, citaxentane, ambricentane, sildenafil, tadalafil and vardenafil.

(Detailed Description of the Preferred Aspects)

In one aspect of the invention, a combination therapy for treating pulmonary arterial hypertension is disclosed. In one embodiment, such co-therapeutic agents are combined with one or more additives, prostacyclin (PGI ₂ , stable analogs thereof (eg iloprost), or derivatives thereof (eg cicletanine)), preferably Administration of an effective amount of an epoprostenol analog, most preferably iloprost. One or more additives may be administered together with prostacyclin, for example in one tablet or capsule, or the additives may be administered separately from prostacyclin. In one preferred embodiment, the prostacyclin is aerosolized. In one embodiment, a second agent is used, such as an endothelin receptor antagonist that relieves vasostate (eg vasodilation) of blood vessels through a mechanism distinct from that of iloprost. Preferably, the endothelin receptor antagonist is selected from the group consisting of bosentan (trade name Tracleer, Actelion), Ambrientane (Myogen), and Sitacentane (Encysive Pharmaceuticals). In another embodiment, the second agent is used to alleviate prostacyclin activity, bioavailability, half-life, or to eliminate undesirable side effects of prostacyclin. In one preferred embodiment, the second medicament is a PDE inhibitor employed to enhance prostacyclin activity, preferably enoximone, milrinone (Primacor), Amrinone (Inocor) , Sildenafil (trade name Viagra), tadalafil (trade name Cialis) and vardenafil (trade name LEVITRA).

Epoprostenol  derivative( Epoprostenol  Derivatives)

Continuous infusion of prostacyclin (trade name Flolan, GlaxoSmithKline) was the primary treatment showing reduced mortality in limited studies in patients with severe pulmonary hypertension. However, its use has been associated with numerous serious side effects (Barst R. J. et al. 1996 N Engl J Med 334: 296-301; Badesch D. B. et al. 2000 Ann Intern Med 132: 425-434). Lack of pulmonary selectivity results in systematic side effects, resistance leads to a gradual increase in dosage, and recurrent infection of the venous catheter can occur. As an alternative, inhaled nitric oxide has lung selectivity, but is less potent than prostacyclin in pulmonary vasculature. Moreover, stopping the continuous inhalation of nitric oxide can cause pulmonary hypertension to return to normal. When designed to combine the efficacy of prostacyclin with an effective amount of inhalation application, aerosolized prostacyclin can be used in patients with acute respiratory distress by continually exerting desirable vasodilation in well-penetrating lungs. It has been found to be an effective pulmonary vasodilator (see Walmrath D. et al. 1993 Lancet 342: 961-962; Walmrath D. et al. 1995 Am J Respir Crit Care Med 151: 724-730; Walmrath D. et al. 1996 Am J Respir Crit Care Med 153: 991-996; Zwissler B. et al. 1996 Am J Respir Crit Care Med 154: 1671-1677). Similar results were obtained in spontaneously breathing patients with pulmonary fibrosis and severe pulmonary hypertension (Olschewski H. et al. 1999 Am J Respir Crit Care Med 160: 600-607).

Three epoprostenol analogs have been studied in the treatment of PAH: treprostinil (trade name Remodulin, United Therapeutics), veraprost, and iloprost. Treprostinol is a stable analog of epoprostenol, which is administered subcutaneously in succession. The increase in dosage was limited to the pain of significant doses. Therefore, many patients do not receive therapeutic doses. Veraprost was also active by oral administration, so it showed effectiveness in PAH studies at 3 and 6 months, but not at 9 or 12 months (see Barst, RJ, J Am Coll Cardiol, June 18, 2003). ; 41 (12): 2119-25). Iloprost can also be administered subcutaneously or by nebulizer. The advantage of delivery by the troubleshooter method is that a smaller amount of the substance reaches the systemic circulation (a "pseudoselective" pulmonary vasodilator). Iloprost is usually given 6 to 9 times per day, which may interfere with the patient's lifestyle, but the frequency of administration is different from other medications that may interact interdependently with a therapeutic effect on pulmonary hypertension through the right mechanism. It can be reduced by administering iloprost together.

Ilofrost ( iloprost )

Iloprost (see US Pat. No. 4,692,464, incorporated herein by reference) is a stable analog of prostatcyclin that is associated with longer duration of vasodilation (see Fitscha P. et al. 1987 Adv Prostaglandin Thronaboxane) Leukot Res 17: 450-454). When sprayed and administered to patients with pulmonary hypertension, its pulmonary vasodilatation efficacy is similar to that of prostacyclin, but its effect lasts for 30 to 90 minutes, compared to only 15 minutes of prostacyclin Hoeper MM et al. 2000 J Am Coll Cardiol 35: 176-182; Olschewski H. et al. 1999 Am J Respir Crit Care Med 160: 600-607; Olschewski H. et al. 1996 Ann Intern Med 124 : 820-824; Gessler T. et al. 2001 Eur Respir J 17: 14-19; Wensel R. et al. 2000 Circulation 101: 2388-2392). Several open-label, unregulated studies in patients with severe pulmonary hypertension have also been shown to result in long-term use of nebulized long-term use of aerosols (Olschewski H. et al. 1999 Am J Respir Crit Care Med 160 : 600-607; Olschewski H. et al. 1996 Ann Intern Med 124: 820-824; Hoeper MM et al. 2000 N Engl J Med 342: 1866-1870; Olschewski H. et al. 1998 Intensive Care Med 24: 631- 634 .; Stricker H. et al. 1999 Schweiz Med Wochenschr 129: 923-927; Olschewski H. et al. 2000 Ann Intern Med 132: 435-443; Beghetti M. et al. 2001 Heart 86: E10-E10). Multi-center randomized placebo control studies in patients with severe PAH have shown enhanced motor performance between patients receiving iloprost versus patients receiving placebo (Olschewski H et al 2002 NEJM 2002; 345: 322-32). 9).

Endothelin  Receptor antagonist ( Endothelin  Receptor Antagonists; ETRA )

Endothelin-1 plays a pathogenic role in pulmonary hypertension and there is increasing evidence that blockade of endothelin receptors may be effective. Endothelin-1 is a potent endogenous angiogenesis inhibitor and smooth muscle mitogen that is overexpressed in the plasma and lung fibers of patients with pulmonary hypertension. There are two classes of endothelin receptors: endothelin A, ET-A and endothelin B, ET-B receptors, which play a significant different role within regular vessel diameters. Binding of endothelin to ET-A receptors on smooth muscle cells causes vasoconstriction, whereas binding of endothelin to ET-B receptors on vascular endothelial cells leads to vasodilation through the production of nitric oxide . The activity of this latter ET-B receptor can be thought of as counter-regulatory and to prevent excessive vasoconstriction.

Thus, another attractive approach to treating pulmonary hypertension may be blocking of these endothelin receptors. Two forms of ETRA have been developed: dual ETRAs that block receptors for both ET-A and ET-B, and selective ETRAs that block only ET-A receptors.

a) Dual Endothelin  Receptor antagonist

First generation ETRAs are nonselective and block both ET-A and ET-B receptors. Bondedane (trade name Tracleer) is the first FDA-approved ETRA (see US Pat. No. 5,292,740, incorporated herein by reference. Two placebo-controlled trials of an endothelin receptor A and B antagonist have been performed. (See Channick RN et al. 2001 Lancet 358: 1119-1123; Rubin LJ et al. 2002 N Engl J Med 346: 896-903.) Although the 6-minute walking test was improved in the entire group, more medication was administered. In one case, the improvement was increased, but hepatotoxicity occurred with higher doses.

b) optional Endothelin  Receptor antagonist

Second generation ETRAs preferentially bind to ET-A receptors rather than ET-B receptors. Currently, there are two selective ETRAs under clinical trials: sitaxsentan and ambrisentan (BSF 208075). Pure endothelin A receptor, citaxentane, is being used in open pilot studies. This showed an improvement in the 6-minute walk test and a 30% reduction in pulmonary vascular resistance (Barst R. J. et al. 2000 Circulation 102: 11-427).

The more potent endothelin compound, TBC3711 (Encysive Pharmaceuticals), entered Phase I testing on December 12, 2001. Such agents have efficacy for treating chronic heart disease and essential hypertension.

There is a small clinical trial using bosentan in patients who have already received other drugs for the treatment of pulmonary hypertension (Hoper MM et al. 2003 in: "Pulmonary Hypertension: Clinical", Abstr. A275, May 18, 2003 Pulmonary Hypertension Roundtable 2002, Phassociation.org/medical/advances in PH / spring 2002). In a preferred embodiment of the present invention, the combination therapy contains iloprost and bosentane which act in combination, preferably interdependently, through separate mechanisms of action to treat pulmonary hypertension. In another preferred embodiment, iloprost is combined with citaxentane. In another preferred embodiment, iloprost is complexed with ambricentane. In another preferred embodiment, iloprost is spray nitrified and administered in combination with bosentane or citaxentane or ambricentane. In another preferred embodiment, iloprost is combined with TBC3711 as a therapeutic agent for pulmonary hypertension.

NOx generation

Endothelial production of nitric oxide results in a decrease in pulmonary hypertension, which is intended to reverse this deficiency by continuous inhalation of nitric oxide (which is effective but difficult to administer) or by increasing the substance for nitric oxide L-arginine. (Nagaya N. et al. 2001 Am J Respir Crit Care Med 163: 887-891) Attempts to supplement with L-arginine are currently in clinical trials.

PDE  Inhibitor

In addition to increasing the supply of nitrogen oxides, attempts have also been made to directly increase the level of cyclic nucleotide second messengers in smooth muscle cells. Sildenafil, used for erectile dysfunction (ED), blocks the enzyme phosphodiesterase type 5 present in the corpus cavernosum and lungs of the penis. This raises the possibility that phosphodiesterase inhibitors, preferably PDE type 5 inhibitors such as sildenafil, may be relatively selective pulmonary vasodilators. There is empirical evidence supporting the inventor's selection of PDE inhibitors as target compounds in combination therapy (see, eg, Michelakis E. et al. 2002 Circulation 105: 2398-2403; Ghofrani H. et al. 2002 Lancet 360: 895-). 900; the entire contents of these documents are incorporated herein by reference).

Although atomized prostacyclin (PGI ₂ ) has been shown for selective pulmonary vasodilation as discussed above, its effect is drastically lowered after spray termination. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibitors has been suggested as a strategy for the amplification of vasodilatory responses to nebulized PGI ₂ . Pulmonary PDE3 / 4 inhibition achieved by endovascular or transbronchial administration of a subthreshold dose of a particular PDE inhibitor entails enhancement in ventilation-perfusion matching and reduction in pulmonary edema formation. While interdependently amplifying the pulmonary vasodilation response to inhaled PGI ₂ . Thus, a combination of nebulized PGI ₂ and PDE3 / 4 may provide a new concept for selective pulmonary vasodilation while maintaining gas exchange in respiratory disorders and pulmonary hypertension (see Schennuly RT et al. 2000 J Pharmacol Exp Ther 292: 512-20). There are several reports of some clinical studies showing that these combinations may be effective in the treatment of pulmonary hypertension (Ghofrani et al. 2002 Crit Care Med 30: 2489-92; Ghofrani et al. 2003 J Am Coll). Cardiol 42: 158-164; Ghofrani et al. 2002 Ann Intern Med 136: 515-22).

The isozyme of cyclic-3 ', 5'-nucleotide phosphodiesterase (PDE) is the azeozyme of cyclic-3', 5'-adenosine monophosphate (cAMP) protein kinase A (PKA) signaling pathway. It is an important ingredient. The superfamily of PDE isozymes consists of at least nine genetypes: PDE1 to PDE9. Some PDE populations are very diverse and consist of several subtypes and numerous PDE isoform-splice variants. PDE isozymes differ not only in the different expressions of various cell types, but also in molecular structure, catalytic properties, intracellular regulation and location, and sensitivity to selective inhibitors.

Phosphodiesterase (PDE) inhibitors are defined herein as specific agents used in the treatment of pulmonary vascular hypertension, which act by blocking the inactivity of cyclic AMP. There are five major quasi-type phosphodiesterases (PDEs); The drugs Enoxymon (inhibits PDE IV) and Milinon® (inhibits PDE IIIc) are most commonly used medicinally. Other phosphodiesterase (PDE) inhibitors are amrinone (Inocor) used to enhance myocardial action, lung and systemic vasodilation, and sildenafil (via Viagra), tadalafil, a selective phosphodiesterase V inhibitor (Trade name Cialis) and vardenafil (trade name LEVITRA).

On the BusinessWire website (webbox / bw.042803 / 231185439.htm), 79% of American males of various ethnic members with erectile dysfunction who participated in clinical trials, 19% of those who received placebo after treatment with investigative medication In comparison, we reported clinical data on tadalafil showing reporting of improved erection status. The new findings in the United States and Puerto Rico are now being presented at the 98th Annual General Meeting of the American Urological Association in Chicago. ED is a disease that affects about 152 million men worldwide.

Tadalafil ™ is a PDE5 inhibitor developed by Lilly ICOS LLC to treat erectile dysfunction. Cardafil is available by prescription in Europe, Australia, New Zealand, and Singapore, and has recently been approved by the US FDA.

Allen Ceftel, PhD, research author and assistant professor of medicine at the College of Urology, University Hospital, Cleveland, says that treatment with Cialis significantly improves erectile dysfunction, including increasing the number of successful attempts at insertion and sexual intercourse and improving erections. He also said, 'I am pleased with the pretty good profile shown by American men of various ethnic members who usually have severe erectile dysfunction.'

In a randomized, placebo-controlled clinical study designed to assess the efficacy and safety of Cialis in men with moderate to severe erectile dysfunction, 207 participants in the United States and Puerto Rico received a 20 mg dose of Cialis or placebo over a 12-week period. Was assigned to receive Four weeks of no treatment were preceded before treatment to determine the criteria for erectile function. Patients were instructed to take the drug as needed at their choice time prior to sexual intercourse, and were informed to confirm that Cialis could work for up to 36 hours. In the study, men were instructed to eat normal meals without suppressing food.

In the study, as determined by the Global Assessment Question, 79% of patients treated with Cialis reported enhanced erection compared to 19% of placebo. In the Sexual Encounter Profile diary, we further found that 77% of vaginal implant attempts in men taking Cialis were successful, compared with 43% in placebo (p> 0.001). ). In addition, men taking Cialis were able to achieve 64% completeness in their sexual trials compared to 23% when taking placebo (p> 0.001). Finally, men taking Cialis achieved statistically significant improvement over all other endpoints of placebo compared to placebo.

The most common reported side effects after treatment (above 5%) in the study were headache, back pain, and upset stomach. The number of patients taking Cialis who could not continue the study because of side effects was 5% compared to 2% who took placebo.

The second clinical study, reported at the annual meeting of the American Urological Association, was designed to assess the long-term safety and well-being of Cialis in 1,173 men with ED, which were phase 3 trials of Cialis conducted in multiple countries around the world. Are already registered These men also included people suffering from a range of complications associated with ED, such as cardiovascular disease and diabetes. Data were obtained from patients who completed treatment for at least one year. All study participants initially received 10 mg of Cialis; During the evaluation period, 83% of these patients (n = 970) increased their dose to 20 mg. Patients were instructed to take medication as needed before having sex.

Similar to other Cialis clinical studies, the most commonly reported side effects after treatment in the studies were headache and upset stomach. Due to side effects, 5% of patients could not continue the study. In these studies, less than 1% were unable to continue because of any personal side effects.

Bayer reported on their website that Levitra (trade name LEVITRA) (vardenafil HC1) was also approved by the US FDA as a medicament for the treatment of erectile dysfunction. Levitra is available at pharmacies across the country.

Myron Murdock, a developer of Levitra and a nationally recognized expert in the field of male sexual dysfunction, a doctor of medicine, said, 'In clinical trials, Levitra was shown to work quickly. More importantly, Levitra showed that most men increased their sexual response at the beginning of taking it and worked consistently over time. '

Bayer and GSK evaluated Levitra in an extensive clinical trial program involving more than 50 clinical trials in more than 5,700 men. As a result of Phase 3 clinical trials, Levitra

(1) help men maintain sufficient erections for satisfactory sex;

(2) provide for the early success and reliable promotion of erection abilities for many men,

(3) acts on men of various ages and races, men with complications such as diabetes, and men whose prostates have been removed;

(4) responded sharply so that men could initiate or respond to sexual stimulation when needed;

(5) It is convenient to use regardless of meal and can take

Showed that.

Levitra is a drug that can be used up to once a day to treat erectile dysfunction. Levitra is only used by prescription. Men who take nitrate medications often used to control chest pain (also known as angina) should not take Levitra. Men who use alpha blockers, which are sometimes prescribed for high blood pressure or prostate symptoms, should not take Levitra. This combination can lower blood pressure to unsafe levels. The most commonly reported side effects are headache, flushing, stuffy nose and runny nose. Men who have had an erection for more than four hours should see their immediate doctor.

For more information on Levitra, refer to the Levitra website, the contents of which are incorporated herein by reference.

Calcium Channel Blockers

According to one aspect of the invention, prostacyclin, preferably iloprost, is administered in combination with a second agent which is a calcium channel blocker. Calcium channel blockers, or antagonists, act to block the penetration of calcium into smooth muscle cells of the heart and arteries to reduce heart contraction and dilate arteries. As the arteries expand, the arterial pressure is reduced so that the heart can pump blood more easily. It also reduces the oxygen demand of the heart. Calcium channel blockers are also useful for treating PPH. Calcium channel blockers are also useful for treating hypertension because they have the effect of lowering blood pressure. Because they lower heart rate, calcium channel blockers can be used to treat rapid heart rhythms such as atrial fibrillation. Calcium channel blockers may also be administered to patients after a heart attack and may help in the treatment of atherosclerosis.

Calcium channel blockers within the scope of this invention include, but are not limited to: amlodipine (US 4,572,909); Bepridil (US 3,962,238); Clenthiazem (US 4,567,175); Diltiazem (US 3,562,257); Pendylin (US 3,262,977); Galopamil (US 3,261,859); Mibepradil (US 4,808,605); Prenylamine (US 3,152,173); Semotiadil (US 4,786,635); Terodidylin (US 3,371,014); Verapamil (US 3,261,859); Aranidipine (US 4,446,325); Bamidipine (US 4,220,649): benidipine (European Patent Application Publication No. 106,275); Silnidipine (US 4,672,068); Eponidipine (US 4,885,284); Elgodipine (US 4,952,592); Felodipine (US 4,264,611); Isradinine (US 4,466,972); Lacidipine (US 4, 801,599); Lercanidipine (US 4,705,797); Manidipine (US 4,892,875); Nicardipine (US 3,985,758); Nifedipine (US 3,485,847); Nibaldipine (US 4,338, 322); Nimodipine (US 3,799,934); Nisoldipine (US 4,154,839); Nitrendipine (US 3,799,934); Cinnarizine (US 2,882,271); Flunarizine (US 3,773,939); Lidofrazine (US 3,267,104); Lomerizin (US. 4,663,325); Bencyclane (Hungarian Patent No. 151, 865); Etaphenone (German patent No. 1,265,758); And perhexiline (British patent No. 1,025,578). All such patents and applications are incorporated herein by reference.

Preferred calcium channel blockers include amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nirenedipine and verapamil, and for example, according to the specific calcium channel blockers, Contains permissible salts.

Compounds to be complexed may be represented by pharmaceutically acceptable salts. For example, if these compounds have at least one basic center, they may form acid addition salts. Also if desired, corresponding acid addition salts with additionally existing basic centers can be formed. Compounds having at least one acid group (eg COOH) also form salts with bases. If the compound of the particular structural formula contains, for example, both carboxyl and amino groups, corresponding internal salts may be further formed.

According to one preferred embodiment of the combination therapy of the present invention, iloprost is administered with a second generation calcium antagonist such as amlodipine. Such combination therapy may be administered as a sustained release dosage form. Preferably, this combination dosage and release form is optimized for hypertensive patients.

While numerous preferred embodiments of the invention and variants thereof have been described in detail, other variations and methods using the combination therapeutics disclosed herein will be apparent to those skilled in the art. It is, therefore, to be understood that various equivalent applications, modifications, and substitutions may be made without departing from the spirit or scope of the invention. It is also to be understood that the invention is not limited to the embodiments illustrated herein for the embodiments, but is limited only by the legitimate interpretation of the claims, including equivalents of components of the appended claims.

All references mentioned herein are incorporated by reference.

Claims (12)

As a therapeutic combination for the treatment of pulmonary arterial hypertension (PAH), it contains at least one additive selected from the group consisting of prostacyclin and endothelin receptor antagonists, PDE inhibitors, and calcium channel blockers, wherein The prostacyclin and one or more additives are provided in an amount sufficient to ameliorate one or more symptoms associated with PAH. The combination therapy according to claim 1, wherein said prostacyclin is selected from the group consisting of iloprost, treprostinol, and veraprost. The combined therapeutic agent according to claim 1, wherein said endothelin receptor antagonist is selected from the group consisting of bosentan, citaxentane, and ambricentan. 2. The combination therapeutic of claim 1, wherein said prostacyclin is iloprost and at least one additive is bosentan. The combination therapy according to claim 4, wherein said iloprost is aerosolized. The combination therapy of claim 1, wherein the one or more additives comprises a PDE inhibitor selected from the group consisting of sildenafil (tradename Viagra), tadalafil (trademark Cialis), and vardenafil (trademark LEVITRA). A method of treating pulmonary arterial hypertension (PAH) comprising administering an effective amount of a prostacyclin and a combination therapeutic comprising at least one additive selected from the group consisting of endothelin receptor antagonists, PDE inhibitors, and calcium channel blockers. 8. The method of claim 7, wherein said prostacyclin is selected from the group consisting of iloprost, treprostinol, and veraprost. 8. The method of claim 7, wherein said endothelin receptor antagonist is selected from the group consisting of bosentan, citaxentane, and ambricentan. 8. The method of claim 7, wherein said prostacyclin is iloprost and at least one additive is bosentan. 8. The method of claim 7, wherein said iloprost is aerosolized. The method of claim 7, wherein said one or more additives comprise a PDE inhibitor selected from the group consisting of sildenafil (tradename Viagra), tadalafil (trademark Cialis), and vardenafil (trademark LEVITRA).